Method for preparing beta keto esters of thiophenes



Patented Mar. 3, 1953 METHOD FOR PREPARING BETAKETO ESTERS OF THIOPHENES August Hi Homeyer, Webster Groves, Ma, as-

signor to Mallinckrodt Chemical Works, St." Louis; Mo., a corporation of Missouri No Drawing. Application November 19, 1947, Serial No. 787,029

3 Claims. 1

Thisinvention relates to esters and more particularly, to beta-keto esters of thiophene derivatives.

Among the several objects of the invention may'be noted the provision of new chemical compounds which are: beta-keto esters of: thiophene and thiophene derivatives; the provisionof i new chemical compounds which are alkylated or aralkylated beta-keto esters of thiophene and thiophene derivatives; and the provision of methods for the economical preparation of the compounds indicated above which are-characterized by high yields, inexpensive and readily procurable reaction materials, and the facility with which these methods may be carriedout. Other objects will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the processes hereinafter described, the scope of the invention being indicated in the following claims.

The present invention relates to beta-keto esters of the following type formula:

in which R, is an alkyl group or hydrogen"; R," is an aralkyl or alkyl group, or hydrogen; RA is an alkyl group; X is an alkyl groupor hydrogen; and metallo-substitut'ed derivatives thereof It. has been found in: accordancewith the present invention that beta-keto esters of thiophene or thiophene derivatives maybe conveniently prepared by simultaneous carbalkoxylation and metallation of 2-thienyl ketones, followed" by acidification or by alkylation or aralkylation either directly or asa separate step.

The simultaneous carbalkoxylation and metallation reaction is shown: the first equation while the alkylation or aralkylation reaction is shown in the second equation:

in' which R representszan alkylrgroup. A metal alcoholate of an alkalimetah MOR',,is used: as a condensing agent inlthefirst reaction. Y inthe second equation may be either a halogen or a sulfate group.

The condensation as shown in:the first-equation'occurson the carbon atom of the alkyl group adjacentthe carbonyl group; It is preferred" that the R radical correspond to the R radical so that unmixed beta-keto esters of thiophene or thiophene' derivatives will be produced by the reaction as shown in the first equation;

Although this reaction may be carried out using an unsymmetrical dialkyl carbonate, it is preferable that symmetrical dialkyl carbonates be used. If unsymmetrical dialkyl carbonatesare used, however, a mixture of: carbalkoxylated compounds and product alcohols may be formed. The reaction of the first equation maybe carried to substantial completion byheating as it progresses, to distill off the productalcohols, R/OH and R"OH. In case" the: original alkali metal alcoholate contains alcohol, such alcohol is likewise removed by this distillation procedure. This procedure, while somewhat optional is highly advantageous in: its improvement inthe yieldiof the carbalkoxylated' compound obtained;

In carrying out the reaction oi the second equation, it is necessary only'to react together the metallo-compound and the alkylating or aralgylating agent in solution in a dialkyl carbonate, an alcohol or any inert reaction medium. A large excess of dialkyl carbonate may be used in the first reaction, the excess serving as the medium for the second reaction. Although it is preferred to use dialkyl carbonate as the sole reaction medium, a portion ofthis may be replaced by inert solvents if desired.

When the intended use of the alkali" metal metallic-substituted compound is the preparation therefrom of an alkyl or aralkyl substituted compound, the alkali metal metallo-substituted compound need not be recovered from the reaction mixture of the first reaction but this reaction column at 150 mm. pressure.

product may be alkylated or aralkylated (as shown in Equation 2) to form the alkylated or aralkylated beta-keto ester, which may then be recovered from the reaction mixture. On the other hand, if carbalkoxylation alone is desired, the metallo group may be replaced by any suitable method, for example, by acidification.

The thenoyl esters of the present invention are useful intermediates for the preparation or pyrazolones, oxirnes, isoxazolones, and the like, The pyrazolones are of value for the preparation of dyestuffs, such as those used in color photography, for example.

, The following examples illustrate certain specfic embodiments of the present invention, but are intended to be illustrative only:

EXAMPLE 1 Ethyl Z-thenoylacetate Sodium metal (13 g.) was dissolved in anhydrous ethyl alcohol (200 ml.) and was distilled to dryness, the final temperature being about 160 C. at 25 mm. pressure. After cooling, diethyl carbonate (300 ml.) was added, and then 2-acetothienone (63 g.) was added slowly with stirring. The reaction mixture became red in color and the temperature rose gradually. After stirring for 30 minutes at 45-55 0., alcohol was fractionated out of the reaction mixture through a When nearly all the alcohol had been removed from the reaction mixture, a dark red solid separated forming a thick slurry. After cooling, the reaction mixture was acidified with glacial acetic acid (40 ml.) and stirred with ice and water. bonate layer was separated, washed and dried.

Distillation from a Claisen flask yielded 73.5 g.

of ethyl thenoylacetate, or 74% of the theoretical yield. It was a yellowish liquid boiling at 128- 134 C. at 2 mm. pressure and having a melting point of 2-7.5 C.

Ethyl thenoylacetate (2 ml.) was mixed with 85% hydrazine hydrate (1 ml.) and one drop of hydrochloric acid and the solution was heated. The resulting 3-(2-thienyl) -5-pyrazolone was purified by recrystallization from alcohol diluted with water and by sublimation in a high vacuum at 140 C. It was a colorless solid melting at hydrochloride (1 g.), alcohol, water and sodium acetate were mixed. Colorless crystals separated and after recrystallization from dilute ethyl al- EXAMPLE 2 Methyl Z-thenoylacetate A mixture of sodium methylate (114 g.) and dimethyl carbonate (720 ml.) was placed in a two liter, three necked flask equipped with stirrer, thermometer, dropping funnel, and a column.

Acetothienone (252 g.) was added dropwise while stirring the sodium methylate-dimethyl carbonate mixture. After minutes, when about .of the ketone had been added, the pot temperature rose to 55 C. and the reaction mixture became too thick to stir.

The diethyl car- More dimethyl carbonate 7 cohol 3-(2-thienyl) isoxazolone melting at 133.5-

137 C. was obtained.

4 (500 ml.) was then added to the reddish mixture. The reaction temperature was maintained at 47 C. while stirring two hours.

During the next 15 hours, methyl alcohol-dimethyl carbonate azeotrope (127 ml.) was distilled off at atmospheric pressure. The head temperature was 63 C. and the pot temperature was found to be C. Then the mixture was cooled, acidified with acetic acid (180 ml.), separated, washed and dried in the usual manner. After recovering 685 ml. of dimethyl carbonate by distillating it off through a column, the keto ester was transferred to a Claisen flask and distilled at 133-134 C. at 3 mm. pressure. The yield was 297.3 g. of methyl 2-thenoylacetate which is a light yellow oily liquid. This was 81% of the theoretical yield.

EXAlVLPLE 3 Methyl Z-thenoylacetate The process as described in Example 2 was carried out with the same apparatus and procedure except that lithium methylate (2 moles) was substituted for the sodium methylate. After separating, washing and drying, the organic layer was distilled yielding methyl 2-thenoylacetate. This product was a light yellow liquid boiling at 133 C. at 2.5 mm. pressure.

EXAMPLE 4 Ethyl Z-thenoylpropiOnate The apparatus and procedure of Example 1 were used and three-tenths molar quantities of the reactants were used as follows: sodium metal (8 g.), ethyl alcohol (120 m1.), diphenylamine (0.5 ml.) as an antioxidant, diethyl carbonate (200 ml.), and 2-propiothienone (42 g.). After the reaction mixture was cooled, acidified, separated, washed and dried in the usual manner, distillation yielded ethyl 2-thenoylpropionate (29.1 g.) It was a yellow oil boiling at 133-134 C. at 4 mm. pressure.

A mixture of ethyl 2-thenoylpropionate (1 ml.) 85% hydrazine hydrate (2 ml.), one drop of hydrochloric acid and alcohol was heated at 80 C., acidified with acetic acid and neutralized with ammonium hydroxide. It yielded 3-(2-thienyl) 4-methyl-5-pyrazolone which was recrystallized from alcohol diluted with water. The colorless solid product melted to a reddish-brown liquid at 205-2065 C.

A mixture of ethyl Z-thenoylpropionate (1 ml.), hydroxylamine hydrochloride (2 g.) dissolved in water, sodium acetate and alcohol to keep all components in solution was heated at 80 C. The oxime of ethyl thenoylpropionate separated as a solid which when recrystallized from diluted alcohol melted at 121-122.5 C.

EXAMPLE 5 Ethyl Z-thenoylpropionate Sodium ethylate was prepared by dissolving sodium metal (5 g.) in specially dried ethyl alcohol (80 ml). and distilling to dryness under reduced pressure. After cooling, diethyl carbonate ml.) together with ethyl 2-thenoylacetate (40 g.) were added and the sodio derivative of ethyl 2-thenoylacetate formed. Methyl iodide (35 g.) was then added to the solution which was at a temperature of approximately 50 C. and a rapid exothermic reaction resulted together with the precipitation of sodium iodide. After warm- .ing for a time, acetic acid and water were added and the organic layer was separated, washed and dried. Distillation from a Claisen tfla'sk :after removing the solvent :gave colorless vapors of ethyl thenoylpropionatetwhich darkened on condensation to a reddish liquid boiling at 128-l30 C. at 3 mm. pressure. The combined fractions weighed 39 g. which was 91% of the theoretical yield.

EXAIVLPLE 6 "Ethyl alpha, aZpha-dimethyl-z-thenoylacetate The ester described in Example 5 was methylated further bythe following reaction. Sodium ethylate was prepared in the usualmanner by dissolving 2 sodium metal (2.5 g.) in .anhydrous ethyl alcohol (40 ml.) and distilling to a dry powder at reduced pressure. A solution of ethyl alpha-2ethenoylpropionate (21.2 g.) in .dry diethyl carbonate (80 ml.) was added to the sodium ethylate, dissolving it to'form a yellowsolution. Methyl iodide g.) was added and warmed and sodium iodide separated promptly. The mixture was then washed with waterand dried, and. the diethylcarbonate was distilled off at 200 mm. pressure, giving ethyl alpha, alphadimethyl-2-thenoylacetate,a liquid which boiled at 125 C. at 4 mm. pressure. The yield was 18.5 g. which was 82% of the theoretical.

A pyrazolone was prepared from hydrazine and the ester. olone crystallized out upon standing, and upon recrystallization from dilute methanol melted at 118-119 C.

Ethyl Z-thenoylbutyrate The apparatus and procedure used to prepare this compound arethe same as those described in Example 1. One-quarter molar quantities were used as follows: sodium metal (6.4 g.) anhydrous ethyl alcohol (100 ml.), diethyl carbonate (150 ml.), redistilled, and Z-butyrothienone (38.5 g.). The product of this reaction was aliquid'boiling at 143-147" C. at3 mm. pressure. The yield was 22.9 g. which was 42.5% of the theoretical.

A mixture of ethyl 2-thenoylbutyrate (1 ml.), hydrazine hydrate (1 ml.), one drop of hydrochloric acid and ethyl alcohol (5 ml.) was heated for one and one-half hours. After adding methanol (3 ml.) and water (3 ml.), and neutralizing with hydrochloric acid, dense white crystals of 3-(2-thienyl)-4-propyl-5-pyrazolone formed. When recrystallized from dilutemethand the melting point was162 C.

EXAMPLE'8 Ethyl Z-thenoylcaprylate Sodium metal (2.5 g.) was disolvedin specially dried ethanol (50 ml.) and ethyl thenoylacetate (20 g.) was added. Then more of the alcohol (50 ml.) was added together with n-hexyl bro mide (22 g.). The reaction mixture was stirred, warmed and brought to a temperature of 70 C. After refluxing 6 hours and keeping overnight the reaction mixture was neutral. It was diluted with water, and the oil was separated. The aqueous layer was then extracted with ether. The combined ether solutions were washed with sodium sulfate solution, dried and then distilled in a Claisen flask. The ethyl 2-thenoylcaprylate product boiled at 174 'C.-at 3 mm. pressure and 3 (2-thieny1)-4,4-dimethyle5-pyrazrretical.

:EXAMPLE'B EthylZ-rthenozjlcaprylate Hexylation of ethyl thenoylacetate without separatingit from its reactionmixtureiswaccomplished as .follows: A one-mole run of ethyl thenoylacetate was .prepared as previously :described in Example 1. After 'ml..of alcohol-had been removed through the column at:15'D .mm. and the dark purple reaction mixture had be- :come extermely thick, the. pot was cooledand 1nhexyl bromide (220 g.) was added. The reaction mixture, still :thick, lightened in "color when heatedon a water bath at 70 :C. for-one-half hour. .115 was allowed tostand-overnight. then while being slowly warmed, the mixture thinned and was refluxed for five hours. During this time an-additional 37ml. of .alcohol were :removed. .The pot wascooled and-the contents acidified with acetic acid(5 ml.) washed xanddried. Distillation from the Claisen flask gave recovered diethyl carbonate (470ml), and then yielded 137.8 g. of ethyl Z-thenoylcaprylate, a light yellow oil boiling. at.183 .C..at 4 mm..pressure. This was 49% o'fthe theoretical yield.

EXAIVIPLE 10 Isobutyl z-thenoylacetate Potassium metal (12.5 .g.) was dissolved in dry isobutyl alcohol ('100iml.) and the solution was distilled to dryness under reduced pressure. When cooled, di-isobutyl carbonate (200 m1.) arid 2-acetothienone (38 g.) were added. The reaction mixture became purple and thick. Isobutanol was removed at reduced pressure,'theibath temperature being 140 .C., the head temperature being 40 C. at 20 mmppressure. 'The'jpot was cooled and the contents acidified withacetic acid (25 ml.). The organiclayer was separated, washed and dried. Distillation from a Claisen flask at reduced pressure removed the di-isobutyl carbonate, and a yield of.27.3 g. of isobutyl 2-thenoylacetate, a yellow liquid boiling at 129 C. at 1 mm. pressure was obtained. "This was 40% of the theoretical.

EXAMPLE 11 Ethyl aZpha-benzyZ-Z-thenoylaceta.te

Sodium me'tal (2.5 g.) was dissolved in specially dried alcohol ml.), and ethylthenoylacetate (20 g.) together'withbenzylchloride (15 g.) were added. Separation of sodium chloride began in a few minutes. The mixture wasrefluxed for 1 hour. A small amount of acetic acid was then added and thereaction mixture was diluted with water, extracted with ether and dried. Distillation from a Claisen flask yielded ethyl alpha-benzyl-2-thenoylacetate, a liquid boiling at 181 C. at 1 mm. pressure. The yield was 22.6 g. which was78% of the theoretical.

EXAMPLE 12 "Ethyl aZpha-cetyl-z-thenoylacetate Sodium metal (2.4.g.) was dissolved inspecially driedalcohol (75 ml.) and the reaction mixture was distilled to dryness at reduced .pressure. The product was suspended in diethyl car- .bonate (ml.) and ethyl thenoylacetate (19.8 -g.) and cetyl bromide (31 g.) .were then. added.

Alcohol and diethyl carbonate were distilled .ofi

until the temperature reached 120 C. Sodium bromide separated while the mixture was refluxed for three and one-quarter hours. At this point a 1 ml. sample of the reaction mixture required 2.2 ml. N/10 HzSOi for neutralization. Refluxing was continued for another one and three-quarter hours, and then the mixture was permitted to stand overnight. Water, ether and acetic acid ml.) were then added. The ether layer was washed, dried and distilled to a 42 g. residue at 100 C. and 5 mm. pressure. This is the exact theoretical weight for ethyl alphacetyl-2-thenoylacetate. A portion of this product in a simple Hickman still was evacuated overnight to remove volatile impurities and then molecularly distilled by heating. Samples of the distilled product which were kept in a refrigerator, as well as samples which were diluted with petroleum ether, crystallized. After crystallizing four times from petroleum ether at 30 C., the purified ethyl alpha-cetyl-2-thenoylacetate was a yellowish-white waxy solid melting at 48 C.

EXAMPLE l3 Methyl 5-methyl-2-thenoylacetate The procedure of Example 1 was followed using one-third molar quantities of sodium methylate, dimethyl carbonate and 5-methyl-2-acetothienone. After adding about one third of the ketone to the stirred dimethyl carbonate-sodium methylate mixture, the pot temperature rose only slightly. Heat was applied to bring the pot to 55 0., and then the heating was stopped, and the remainder of the ketone was added dropwise. The pot temperature continued to rise to 60 C. and then started to drop, and heat was applied to maintain the temperature at 55 C. After adding all the ketone in twenty-five minutes, the mixture was stirred for one and one-quarter hours at 55 C. Then during the next one and one-quarter hours, methyl alcohol dimethyl carbonate mixture (58 ml.) was distilled off at 63.5- 88 C. The reaction mixture became pink at the beginning, and then gradually darkened to a brick red, but did not thicken. It was cooled, acidified, separated, and washed and dried over sodium sulfate. Distillation from a Claisen flask yielded 46.6 g. of methyl 5-meth'yl-2-thenoylacetate, a light yellow oily liquid boiling at 143 C. at 2.5 mm. pressure. This was 71% of the theoretical yield.

A mixture of methyl 5-methyl-2-thenoy1acetate (2 ml.), phenyl hydrazine (1.5 ml.), ethyl alcohol (5 ml.) and one drop of hydrochloric acid was heated on the steam bath for one hour. When it was cooled and petroleum ether was added a solid which was l-phenyl 3-(5-methyl- 2-thienyl)-5-pyrazolone, separated. After recrystallization from a mixture of ethyl alcohol and methanol it melted at 136-137.5 C.

It will be understood that the thiophene ring may contain inert constituents other than the alkyl groups represented b X in the above formulas.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above processes and products without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

I claim: 1. The process comprising mixing a 2-thienyl ketone of the following type formula:

in which R is selected from the group consisting of alkyl radicals and hydrogen, and X is selected from the group consisting of lower alkyl radicals and hydrogen, with an anhydrous alkali metal alcoholate and a lower symmetrical dialkyl carbonate, whereby one of the hydrogens of the CH2 group is replaced by a carbalkoxy group and the other hydrogen is replaced by an alkali metal, and linking by an alkyl linkage a radical selected from the group consisting of an alkyl radical and a benzyl radical by mixing said reaction mixture with a compound of said radical attached to a substance selected from the group consisting of halogen and sulfate.

2. The process comprising mixing a 2-thienyl ketone of the following type formula:

in which R. i selected from the group consisting of alkyl radicals and hydrogen, and X is selected from the group consisting of lower alkyl radicals and hydrogen, with an anhydrous alcohol-free alkali metal alcoholate and a lower symmetrical dialkyl carbonate in quantities sufficient to function as reagent and reaction medium, whereby one of the hydrogens of the CH2 group is replaced by a carbalkoxy group and the other hydrogen is replaced by an alkali metal, and removing alcohol, and linking by an alkyl linkage a radical selected from the group consisting of an alkyl radical and a benzyl radical by mixing said reaction mixture with a compound of said radical attached to a substance selected from the group consisting of halogen and sulfate.

3. The process comprising mixing a 2-thienyl ketone of the following type formula:

XU-C 0-0132-11 in which R is selected from the group consisting of alkyl radicals and hydrogen, and X is selected from the group consisting of lower alkyl radicals and hydrogen, with an anhydrous alcoholfree alkali metal alcoholate and a large excess of a lower symmetrical dialkyl carbonate the quantities thereof being sufficient to function as reagent and reaction medium, and continuously removing alcohol from the reaction mixture, whereby one of the hydrogens of the CH2 group is replaced by a carbalkoxy group and the other hydrogen is replaced by an alkali metal, and removing alcohol, and linking by an alkyl linkage a radical selected from the group consisting of an alkyl radical and a benzyl radical by mixing said reaction mixture with a compound of said radical attached 'to a substance selected from the group consisting of halogen and sulfate.

AUGUST H. HOMEYER.

(References on following page) Number Number REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Steinkopf: Chemie des Thiophens, page 21. Powers: Advancing Fronts in Chemistry, vol. 2, p. 33, Reinhold, N. Y., 1946. 5 Whitemore: Organic Chemistry, pp. 884;, 893,

Name Date Van Nostrand, N. Y., 1937. Havas 193,5 Richter: Organic Chemistry, pp. 649-650, W m r u y 1 2 Wj1ey N y 1933 Wallmgmd 1945 Steinkopf: Chemie des Thiophens, pp. 13, 71, Porter 81 6, 1948 10 Edwards Lithoprint (1941). Turnbull May 25, 1948 FOREIGN PATENTS Country Date Great Britain June 19, 1939 

1. THE PROCESS COMPRISING MIXTURE A 2-THIENYL KETONE OF THE FOLLOWING TYPE FORMULA: 